Turning Point 2013

Searching for Similarities

Certain breast and ovarian cancers have genetic commonalitiesBy Robert Levy

Ovarian cancer and breast cancer may both arise in women, but they aren't exactly sister diseases. Aside from the fact that they begin in an organ and gland related to reproduction, they don't initially appear to have much in common.

Consider: Breast cancers are often diagnosed at an early stage of growth, while ovarian cancers usually aren't detected until they're more advanced. When breast cancers spread to other parts of the body, they tend to favor the bones, lungs, or liver; ovarian cancers usually travel to the surface of organs in the abdomen.

Yet for many years there have been hints that a few specific types of breast and ovarian cancer do have a distant kinship. The evidence isn't necessarily found in the way the diseases behave, how reliably they're detected in screening tests, or how they metastasize. Rather, the common element seems to lie at the bedrock level of their DNA — in inherited gene mutations that allow tumor cells to form and take root in the body.

The first suggestion of a genetic link came in the 1990s among studies of women who inherited mutations in the genes BRCA1 or BRCA2. Researchers found that such women had not only an increased risk of developing breast cancer — BRCA stands for BReast CAncer susceptibility — but also an increased risk of ovarian cancer (and certain other cancers).

"We know that women with inherited BRCA1 or 2 mutations have about a 40-80 percent chance of developing breast cancer during their lifetimes, and a much-increased chance of developing ovarian cancer as well," says Judy Garber, MD, MPH, director of Dana-Farber's Center for Cancer Genetics and Prevention. "In both cases, it's far higher than the normal lifetime risk for these diseases.

"The BRCA1 and 2 data told us that, for this group of women, breast and ovarian cancers may develop at least partly through the same genetic pathways," she continues. "The question then became, 'What is the mechanism by which mutations in BRCA1 or 2 lead to cancer?'"

Subsequent research — much of it led by Dana-Farber's David Livingston, MD — revealed that the BRCA genes normally protect against cancer by repairing damaged sections of DNA within cells. When mutations hinder BRCA from doing its job, the damage persists, wrecking the cells' instructions for orderly division, and pushing cells one step closer to becoming cancerous.

If BRCA-related breast and ovarian cancers had a common cause, there might be a common approach to preventing them or catching them at the earliest stage. Women who test positive for BRCA1 or 2 mutations are often advised to receive more frequent screening tests: mammograms for breast cancer; ultrasound, blood tests, and clinical exams for ovarian cancer.

One preventive option is pre-emptive surgery — removal of the breasts, ovaries, and fallopian tubes to deny cancer a starting point. Another option is medicinal: oral contraceptives reduce ovarian cancer risk in women carrying a BRCA1 or 2 mutation, but their effect on breast cancer risk is unclear.

Even as doctors and patients pursued these strategies, research was beginning to show that such cancers could also be treated by the same type of chemotherapy drug. "There have been consistent data over a long period of time that platinum-based drugs, such as cisplatin, work better against ovarian cancers in women carrying BRCA mutations than against ovarian tumors in women without these mutations," Dr. Garber explains. "Therefore, we decided to ask whether platinum drugs could also be more effective in certain breast cancers with BRCA mutations."

She and her associates first focused on "triple-negative" breast cancer, named for its ability to grow without three major growth-stimulating hormones and proteins. Most BRCA1-mutated breast cancers are triple-negative. With colleagues Daniel Silver, MD, and Andrea Richardson, MD, PhD, Dr. Garber led the first clinical trial in which patients with triple-negative breast cancer were treated with four doses of cisplatin before surgery. In 22 percent of the participants, no traces of cancer remained following surgery.

Drs. Richardson, Silver, and others carried the research a step further when they examined tumor tissue removed from the patients who participated in the trials. Their analysis revealed a "biomarker" — a pattern of missing copies of chromosomes within the tumor cells – that indicates which triple-negative cancers are likely to succumb to platinum-based therapies.

The research represents an important advance for treatment of triple-negative breast cancer, the researchers say. Although the disease can often be treated successfully by standard chemotherapy drugs, patients who aren't helped by such drugs have had few good alternatives. Researchers have opened a clinical trial comparing platinum to standard chemotherapy for newly diagnosed breast cancers in women with BRCA1 or 2 mutations.

The Ovarian Connection

These genetic parallels are propelling new approaches to ovarian cancer treatment, as well.

"We know that triple-negative breast cancers often have a mutation in BRCA1," says Ursula Matulonis, MD, medical director of Gynecologic Oncology at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC). "And patients with high-grade serous ovarian cancer — the most common form of ovarian cancer — often carry inherited mutations in either BRCA1 and 2. This led researchers to test whether drugs aimed at these specific genetic weaknesses would be effective against both diseases."

The logic behind this approach is easily grasped: Cancer cells with defective BRCA genes may proliferate rapidly, but they're also uniquely vulnerable, because the lack of able-bodied BRCA hampers their ability to repair DNA damage. Some of the first drugs employed to take advantage of this vulnerability were platinum agents such as cisplatin, which damage DNA.

There are other DNA-repair systems in cells, but they're no substitute for functioning BRCA. Blocking these systems with a drug compound might hamper DNA repair so severely that the tumor cell could no longer survive. It would be like knocking another leg off a table that is already missing one.

A newer class of drugs known as PARP inhibitors is designed to do just that. By interfering with an enzyme known as PARP, which is needed for proper DNA repair, these drugs can further erode the DNA-repairing abilities of tumor cells with non-functional BRCA genes.

PARP inhibitors may work in tandem with other targeted drugs. Scientists at Beth Israel Deaconess Medical Center ran studies combining a PARP inhibitor and an inhibitor of another enzyme, known as PI3 kinase, in mice. They found that the drug duo produced extensive killing of cancer cells in the animals, in some cases leading to cures.

With these findings as a base, Dr. Matulonis and her colleagues have opened a phase 1 clinical trial of the two inhibitors for women with high-grade ovarian cancer or triple-negative breast cancer that has recurred after treatment, and for breast or ovarian cancer patients whose tumors carry a BRCA1 or BRCA2 mutation. This early-phase trial, largely funded by a Stand Up To Cancer grant, is being led by Dana-Farber, which is collaborating on the effort with several other major cancer centers nationwide. The clinical trial aims to determine the correct dose of the drugs and monitor their safety. Later phases will focus on the drugs' effectiveness.

"We're reaching the point where we need to start thinking about these two diseases in a like-minded way because of their underlying genetic similarities," Dr. Matulonis remarks.

Dealing a Double Blow

The notion of using drugs to deliver a finishing blow to cancer cells whose DNA damage-repair machinery is already weakened – a concept known as synthetic lethality — is being explored in several types of cancer, including breast and ovarian. "The analogy of the table with a missing leg is becoming increasingly appealing in designing treatments," says J. Dirk Iglehart, MD, director of the Susan F. Smith Center for Women's Cancers at DF/BWCC.

Geoffrey Shapiro, MD, PhD, and Alan D'Andrea, MD, are exploring whether cancer cells are susceptible to drugs that target DNA repair mechanisms even if the cells' BRCA genes aren't mutated. Their strategy is two-fold: cripple BRCA1 with a drug that blocks an enzyme needed by BRCA1, and add a PARP inhibitor to further impede DNA-repair. The approach worked so well in the laboratory that it is now being used in a phase 1 clinical trial for patients with lung, breast, ovarian, or other cancers not linked to BRCA.

Drs. Garber, Shapiro, and D'Andrea are taking a similar tack in studies involving two drugs. One is a very new enzyme inhibitor that targets a key step in BRCA1 function; the second is the older drug bortezamib, which has traditionally been used to treat multiple myeloma. The team is exploring whether these drugs can prevent a DNA-repair pathway from switching on, and then combining it with a PARP inhibitor to gauge its effect on different types of cancer cells.

The promise of these approaches is spurring a range of studies.

"In an application for a major research grant from the National Cancer Institute, DF/BWCC scientists and clinicians came together to create two projects that involve new treatments for triple-negative breast cancer," says Eric Winer, MD, director, DF/BWCC's Breast Oncology Center, who has led trials of a variety of breast cancer therapies. "One of these involves approaches developed by Drs. D'Andrea and Shapiro, and the other is based on work by Dr. Kornelia Polyak."

Adds Dr. Iglehart, "As we learn more about the genomic landscape of breast and ovarian cancers, we're likely to discover more points of similarity between the two diseases. That opens the possibility of new approaches to treatment."